Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof

ABSTRACT

The present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof and a process for making thereof. The compounds have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention also provides intermediate compounds useful in the process, as well as final products produced by the process, and salts or prodrugs thereof. The invention further provides a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases comprising administering an effective amount of a compound according to the invention to a patient in need thereof.

RELATED APPLICATIONS

This application is a reissue application of U.S. patent applicationSer. No. 10/041,160, filed Jan. 8, 2002, now U.S. Pat. No. 6,951,937 andclaims the benefit of priority under 35 U.S.C. 119(e) to U.S.Provisional Application No. 60/244,655 filed on Nov. 1, 2000 and U.S.Provisional Application No. 60/259,859 filed on Jan. 8, 2001 which areis herein incorporated in their entirety by reference.

FIELD OF INVENTION

The present invention relates to nitrogen-containing heterocycliccompounds and pharmaceutically acceptable salts or prodrugs thereofwhich have inhibitory activity on the phosphorylation of kinases, whichinhibits the activity of such kinases. The invention also relates to aprocess for making nitrogen-containing heterocyclic compounds andintermediate compounds thereof, and pharmaceutically acceptable salts orprodrugs thereof. The invention further relates to a method of using thecompounds of the present invention by inhibiting kinases and treatingdisease states in a mammal by inhibiting the phosphorylation of kinasesby administering an effective amount of a compound according to theinvention to a patient in need thereof.

BACKGROUND OF THE INVENTION

Platelet derived growth factor (PDGF) is known to act as an aggravatingfactor for cell-proliferative diseases such as arteriosclerosis,vascular reobstruction after percutaneous coronary angioplasty andbypass operation, cancer, glomerulonephritis, glomerulosclerosis,psoriasis and articular rheumatism. See Cell, 46: 155-169 (1986);Science, 253: 1129-1132 (1991); Nippon Rinsho (Japanese J. of ClinicalMedicine), 50: 3038-3045 (1992); Nephrol Dial Transplant, 10: 787-795(1995); Kidney International, 43 (Suppl. 39): 86-89 (1993); Journal ofRheumatology, 21: 1507-1511 (1994); Scandinavian Journal of Immunology,27: 285-294 (1988).

Quinazoline derivatives which are useful as drugs,N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamideis described as a bronchodilator in South African Patent No. 67 06512(1968). Dimethoxyquinazoline derivatives are described as inhibitors ofphosphorylation of epidermal growth factor (EGF) receptor in JapanesePublished Unexamined Patent Application No. 208911/93 and WO 96/09294.Quinoline derivatives having benzodiazepin receptor agonist activity aredescribed in Pharmacology Biochemistry and Behavior, 53, 87-97 (1996)and European Journal of Medicinal Chemistry, 31, 417-425 (1996), andquinoline derivatives which are useful as anti-parasite agents aredescribed in Indian Journal of Chemistry, 26B: 550-555 (1987).

Inhibitors of phosphorylation of PDGF receptor so far known includebismono- and bicyclic aryl compounds and heteroaryl compounds (WO92/20642), quinoxaline derivatives. See Cancer Research, 54: 6106(1994), pyrimidine derivatives (Japanese Published Unexamined PatentApplication No. 87834/94) and dimethoxyquinoline derivatives Abstractsof the 16th Annual Meeting of the Pharmaceutical Society of Japan(Kanazawa) (1996), 2: 275; 29(C2): 15-21. Nitrogenous heterocycliccompounds are also described in WO 98/14431 published on Apr. 9, 1998.The WO document describes various processes for making such compoundsand phosphorylation inhibition activity thereof.

SUMMARY OF THE INVENTION

The present invention is directed to nitrogen-containing heterocycliccompounds and pharmaceutically acceptable salts thereof. These compoundshave inhibitory activity on the phosphorylation of kinases, whichinhibits the activity of the kinases. More particularly, importantkinase inhibition according to the present invention is of receptortyrosine kinases including platelet-derived growth factor (PDGF)receptor, Flt3, CSF-1R, epidermal growth factor receptor (EGRF),fibroblast growth factor (FGF), vascular endothelial growth factorreceptor (VEGFR) and others. Another class of kinase inhibitionaccording to the invention is inhibitory activity nonreceptor tyrosinekinases including src and abl, and the like. A third class of kinaseinhibition according to the invention is inhibitory activity towardserine/threonine kinases, including such kinases as MAPK, MEK and cyclindependent kinases (CDKs) that mediate cell proliferation, AKT and CDKsuch that mediate cell survival and NIK that regulate inflammatoryresponses. Inhibition of such kinases can be used to treat diseasesinvolving cell survival, proliferation and migration, includingcardiovascular disease, such as arteriosclerosis and vascularreobstruction, cancer, glomerulosclerosis fibrotic diseases andinflammation, as well as the general treatment of cell-proliferativediseases.

One aspect of the present invention relates to a process for makingnitrogen-containing heterocyclic compounds represented by formula A asfollows:

wherein

-   R¹ is a member selected from the group consisting of:

—CN, —O—C₁₋₈ alkyl that is straight or branched chained, —O-phenyl,—O-naphthyl, —O-indolyl and —O-isoquinolinyl;

-   R² and R⁴ are each independently a member selected from the group    consisting of:

hydrogen, —O—CH₃, —O(—CH₂)—CH₃, —O(—CH₂)₂ —CH₃, —O—CH₂—CH═CH₂,—O—CH₂—C≡CH and —O(—CH₂)_(n)—R³; wherein one of the R² and R⁴ groups is—O(—CH₂)_(n)—R³ and the remaining R² or R⁴ group is other than—O(—CH₂)_(n)—R³;

-   n is 2 to 5;-   R³ is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-phenyl), —CN

-    and a 4 to 10 member mono or bicyclic saturated, partially    unsaturated or fully unsaturated heterocyclic ring system having at    least 1 nitrogen atom and from 0 to 3 additional hetero atoms    selected from the group consisting of O, N, and S, wherein the ring    system may be unsubstituted or may be substituted by 1 to 4 members    selected from the group consisting of H, halo, halo loweralkyl,    lower alkyl, lower alkynyl, lower acyl, lower alkoxy, hydroxy,    nitro, amino and the like, wherein the ring system may be attached    directly to the neighboring methylene group or may be attached via    an ether bond,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another aspect of the invention relates to a process for the productionof such compounds wherein R³ is a member selected from the groupconsisting of:

-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another aspect of the invention relates to a process for makingcompounds according to formula A above of such compounds wherein R¹ is amember selected from the group consisting of CN, —O-methyl, —O-ethyl,—O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl,1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy, and position isomers and homologs thereof, and allpharmaceutically acceptable isomers, salts, hydrates, solvates andprodrug derivatives of such compounds.

Still another aspect of the invention relates to a process for makingpharmaceutically acceptable salts of the compounds according to formula(A) which include pharmaceutically acceptable acid addition salts, metalsalts, ammonium salts, organic amine addition salts, amino acid additionsalts, and the like.

Another aspect of invention relates to a process for making compoundsaccording to formula A(1) and formula A(2) as follows:

wherein

-   R¹ is a member selected from the group consisting of:

—CN, —O—C₁₋₈ alkyl that is straight or branched chained, —O-phenyl,—O-naphthyl, —O-indolyl and —O-isoquinolinyl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another aspect of the invention relates to a process for makingcompounds according to formula A(1) or A(2) above wherein R¹ is—O-isopropyl or CN, n is 2 or 3, and R³ is a cyclic amine, as well asposition isomers and homologues thereof, and all pharmaceuticallyacceptable isomers, salts, hydrates, solvates and prodrug derivatives ofsuch compounds.

Still another aspect of the invention relates to a process for preparingcompounds according to formula A(1) or A(2) wherein n is 3, R¹ is—O-isopropyl or CN and R³ is a member selected from the group consistingof:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another aspect of the invention relates to a process for preparingcompounds according to formula A(1) or A(2) wherein n is 3, R¹ is—O-isopropyl or CN and R³ is a 4-6 membered saturated cyclic amineselected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another aspect of the present invention relates to a process for makingcompounds and pharmaceutically acceptable salts thereof which inhibit orprevent inhibition of phosphorylation of at least one PDGF receptor byat least one tyrosine kinase. Such PDGF receptor kinase inhibition canhinder abnormal cell growth and cell wandering, and thus such compoundsare useful for the prevention or treatment of cell-proliferativediseases such as arteriosclerosis, vascular reobstruction, cancer andglomerulosclerosis.

Other aspects, objects, features and advantages of the present inventionwould be apparent to one of ordinary skill in the art from the followingdetailed description illustrating the preferred embodiments of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkenyl” refers to a trivalent straight chain or branchedchain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”)refers to a straight or branched chain aliphatic radical that includesat least two carbons joined by a triple bond. If no number of carbons isspecified alkenyl and alkinyl each refer to radicals having from 2-12carbon atoms.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a substituted or unsubstitutedmember selected from the group consisting of: a stable monocyclic ringwhich is aromatic ring (“aryl”) having six ring atoms; a stablemonocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring;a stable bicyclic ring structure having a total of from 7 to 12 ringatoms in the two rings wherein the bicyclic ring structure is selectedfrom the group consisting of ring structures in which both of the ringsare aromatic, ring structures in which one of the rings is aromatic andring structures in which both of the rings are non-aromatic; and astable tricyclic ring structure having a total of from 10 to 16 atoms inthe three rings wherein the tricyclic ring structure is selected fromthe group consisting of: ring structures in which three of the rings arearomatic, ring structures in which two of the rings are aromatic andring structures in which three of the rings are non-aromatic. In eachcase, the non-aromatic rings when present in the monocyclic, bicyclic ortricyclic ring structure may independently be saturated, partiallysaturated or fully saturated. Examples of such carbocyclic ringstructures include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, ortetrahydronaphthyl (tetralin). Moreover, the ring structures describedherein may be attached to one or more indicated pendant groups via anycarbon atom which results in a stable structure. The term “substituted”as used in conjunction with carbocyclic ring structures means thathydrogen atoms attached to the ring carbon atoms of ring structuresdescribed herein may be substituted by one or more of the substituentsindicated for that structure if such substitution(s) would result in astable compound.

The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected fromloweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano,hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,carboalkoxy and carboxamide, including but not limited to carbocyclicaryl, heterocyclic aryl, and biaryl groups and the like, all of whichmay be optionally substituted. Preferred aryl groups include phenyl,halophenyl, loweralkylphenyl, naphthyl, biphenyl, phenanthrenyl andnaphthacenyl.

The term “arylalkyl” which is included with the term “carbocyclic aryl”refers to one, two, or three aryl groups having the number of carbonatoms designated, appended to an alkyl group having the number of carbonatoms designated. Suitable arylalkyl groups include, but are not limitedto, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, andthe like, all of which may be optionally substituted.

As used herein, the term “heterocyclic ring” or “heterocyclic ringsystem” is intended to mean a substituted or unsubstituted memberselected from the group consisting of stable monocyclic ring having from5-7 members in the ring itself and having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S; a stable bicyclic ringstructure having a total of from 7 to 12 atoms in the two rings whereinat least one of the two rings has from 1 to 4 hetero atoms selected fromN, O and S, including bicyclic ring structures wherein any of thedescribed stable monocyclic heterocyclic rings is fused to a hexane orbenzene ring; and a stable tricyclic heterocyclic ring structure havinga total of from 10 to 16 atoms in the three rings wherein at least oneof the three rings has from 1 to 4 hetero atoms selected from the groupconsisting of N, O and S. Any nitrogen and sulfur atoms present in aheterocyclic ring of such a heterocyclic ring structure may be oxidized.Unless indicated otherwise, the terms “heterocyclic ring” or“heterocyclic ring system” include aromatic rings, as well asnon-aromatic rings which can be saturated, partially saturated or fullysaturated non-aromatic rings. Also, unless indicated otherwise the term“heterocyclic ring system” includes ring structures wherein all of therings contain at least one hetero atom as well as structures having lessthan all of the rings in the ring structure containing at least onehetero atom, for example bicyclic ring structures wherein one ring is abenzene ring and one of the rings has one or more hetero atoms areincluded within the term “heterocyclic ring systems” as well as bicyclicring structures wherein each of the two rings has at least one heteroatom. Moreover, the ring structures described herein may be attached toone or more indicated pendant groups via any hetero atom or carbon atomwhich results in a stable structure. Further, the term “substituted”means that one or more of the hydrogen atoms on the ring carbon atom(s)or nitrogen atom(s) of the each of the rings in the ring structuresdescribed herein may be replaced by one or more of the indicatedsubstituents if such replacement (s) would result in a stable compound.Nitrogen atoms in a ring structure may be quaternized, but suchcompounds are specifically indicated or are included within the term “apharmaceutically acceptable salt” for a particular compound. When thetotal number of O and S atoms in a single heterocyclic ring is greaterthan 1, it is preferred that such atoms not be adjacent to one another.Preferably, there are no more that 1 O or S ring atoms in the same ringof a given heterocyclic ring structure.

Examples of monocyclic and bicyclic heterocyclic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocyclic ringstructures.

As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms “halo” or “halogen” as used herein refer to Cl, Br, F or Isubstituents. The term “haloalkyl”, and the like, refer to an aliphaticcarbon radicals having at least one hydrogen atom replaced by a Cl, Br,F or I atom, including mixtures of different halo atoms. Trihaloalkylincludes trifluoromethyl and the like as preferred radicals, forexample.

The term “methylene” refers to —CH₂—.

The term “leaving group” in the definition of L₁, L₂ and Q includehalogen atoms, substituted or unsubstituted alkoxy groups, substitutedor unsubstituted aryloxy groups, substituted or unsubstituted alkylthiogroups, substituted or unsubstituted alkylsulfinyl groups, substitutedor unsubstituted alkylsulfonyl groups, substituted or unsubstitutedalkylsulfonyloxy groups, substituted or unsubstituted arylsulfonyloxygroups, and the like. The halogen atom, alkoxy group, aryloxy group,alkylthio group and alkylsulfinyl group have the same meanings asdefined above, respectively, the alkyl moiety of the alkylsulfonyl groupand alkylsulfonyloxy group has the same meaning as the alkyl groupdefined above, and the aryl moiety of the arylsulfonyloxy group has thesame meaning as the aryl defined above. Examples of the substituentinclude halogen atoms, alkyl groups, a nitro group, and the like, andthe halogen atom has the same meaning as the halogen atom defined above.Other examples include methane sulfonate and p-toluene sulfonate.

The term “pharmaceutically acceptable salts” include salts of compoundsderived from the combination of a compound and an organic or inorganicacid. These compounds are useful in both free base and salt form. Inpractice, the use of the salt form amounts to use of the base form; bothacid and base addition salts are within the scope of the presentinvention.

“Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

This invention also encompasses prodrug derivatives of the compoundscontained herein. The term “prodrug” refers to a pharmacologicallyinactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous or enzymatic, within the organismto release the active drug. Prodrugs are variations or derivatives ofthe compounds of this invention which have groups cleavable undermetabolic conditions. Prodrugs become the compounds of the inventionwhich are pharmaceutically active in vivo, when they undergo solvolysisunder physiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry ofDrug Design and Drug Action, pp. 352-401, Academic Press, San Diego,Calif., 1992). Prodrugs commonly known in the art include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acids with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine, or basic groups reacted to form an acylated base derivative.Moreover, the prodrug derivatives of this invention may be combined withother features herein taught to enhance bioavailability.

“Biological property” for the purposes herein means an in vivo effect orantigenic function or activity that is directly or indirectly performedby a compound of this invention that are often shown by in vitro assays.Effector functions include receptor or ligand binding, any enzymeactivity or enzyme modulatory activity, any carrier binding activity,any hormonal activity, any activity in promoting or inhibiting adhesionof cells to an extracellular matrix or cell surface molecules, or anystructural role. Antigenic functions include possession of an epitope orantigenic site that is capable of reacting with antibodies raisedagainst it.

The present invention relates to a process for makingnitrogen-containing heterocyclic compounds represented by formula A asfollows:

wherein

-   R¹ is a member selected from the group consisting of:

—CN, —O—C₁₋₈ alkyl that is straight or branched chained, —O-phenyl,—O-naphthyl, —O-indolyl and —O-isoquinolinyl;

-   R² and R⁴ are each independently a member selected from the group    consisting of:

hydrogen, —O—CH₃, —O(—CH₂)—CH₃, —O(—CH₂)₂ —CH₃, —O—CH₂—CH═CH₂,—O—CH₂—C≡CH and —O(—CH₂)_(n)—R³; wherein one of the R² and R⁴ groups is—O(—CH₂)_(n)—R³ and the remaining R² or R⁴ group is other than—O(—CH₂)_(n)—R³;

-   n is 2 to 5;-   R³ is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-phenyl), —CN

-    and a 4 to 10 member mono or bicyclic saturated, partially    unsaturated or fully unsaturated heterocyclic ring system having at    least 1 nitrogen atom and from 0 to 3 additional hetero atoms    selected from the group consisting of O, N, and S, wherein the ring    system may be unsubstituted or may be substituted by 1 to 4 members    selected from the group consisting of H, halo, halo loweralkyl,    lower alkyl, lower alkynyl, lower acyl, lower alkoxy, hydroxy,    nitro, amino and the like, wherein the ring system may be attached    directly to the neighboring methylene group or may be attached via    an ether bond,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A preferred process is a process for the production of such compoundswherein R³ is a member selected from the group consisting of:

-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A particularly preferred process is a process for making compoundsaccording to formula A above wherein R¹ is a member selected from thegroup consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,—O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy,4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy, and position isomers andhomologs thereof, and all pharmaceutically acceptable isomers, salts,hydrates, solvates and prodrug derivatives of such compounds. Morepreferred is a process for making compounds wherein n is 2 or 3 and R¹is —O-isopropyl or CN and R³ is a cyclic amine.

The process also provides for making pharmaceutically acceptable saltsof the compounds according to formula (A) which include pharmaceuticallyacceptable acid addition salts, metal salts, ammonium salts, organicamine addition salts, amino acid addition salts, etc. Examples of thepharmaceutically acceptable acid addition salts of the compounds offormula (A) are inorganic acid addition salts such as hydrochloride,sulfate and phosphate, and organic acid addition salts such as acetate,maleate, fumarate, tartrate, citrate and methanesulfonate. Examples ofthe pharmaceutically acceptable metal salts are alkali metal salts suchas sodium salt and potassium salt, alkaline earth metal salts such asmagnesium salt and calcium salt, aluminum salt and zinc salt. Examplesof the pharmaceutically acceptable ammonium salts are ammonium salt andtetramethyl ammonium salt. Examples of the pharmaceutically acceptableorganic amine addition salts include heterocyclic amine salts such asmorpholine and piperidine salts. Examples of the pharmaceuticallyacceptable amino acid addition salts are salts with lysine, glycine andphenylalanine. The process also provides for making pharmaceuticallyacceptable isomers, hydrates, solvates and prodrug derivatives of thecompounds according to formula (A) and would be apparent to one ofordinary skill in the art.

The present process invention can be readily adapted to make othercompounds in the art, such as the nitrogenous heterocyclic compoundsdescribed in WO 98/14431 published on Apr. 9, 1998. Accordingly, thepresent invention also provides for making such compounds using thepresent procedures or readily apparent variations thereon.

In a preferred embodiment the invention provides a process for makingcompounds according to formula A(1) and formula A(2) as follows:

wherein

-   R¹ is a member selected from the group consisting of:

—CN, —O—C₁₋₈ alkyl that is straight or branched chained, —O-phenyl,—O-naphthyl, —O-indolyl and —O-isoquinolinyl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A particularly preferred process is a process for making compoundsaccording to formula A(1) or A(2) above wherein R¹ is —O-isopropyl orCN, n is 2 or 3, and R³ is a cyclic amine, as well as position isomersand homologues thereof, and all pharmaceutically acceptable isomers,salts, hydrates, solvates and prodrug derivatives of such compounds.

A more preferred is a process for making compounds according to formulaA(1) or A(2) wherein n is 3, R¹ is —O-isopropyl or CN and R³ is a memberselected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Further preferred is such a process wherein n is 3, R¹ is —O-isopropylor CN and R³ is a 4-6 membered saturated cyclic amine selected from thegroup consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Most preferable is a process for making such compounds of formula A(1)or A(2) wherein n is 3, R¹ is —O-isopropyl or CN and R³ is N-piperidineor N-pyrrolidine.

The pharmaceutically acceptable salts of the compounds according toformula (A) include pharmaceutically acceptable acid addition salts,metal salts, ammonium salts, organic amine addition salts, amino acidaddition salts, etc.

The present invention process is not limited by the above listedcompounds, but includes intermediates for making such compounds or otherrelated compounds. Analogs of the bicyclic compounds are contemplatedand would be apparent to one of ordinary skill in the art.

The compounds may be prepared using methods and procedures generally asdescribed below, however other leaving groups may be utilized.

The present invention is directed to a process for preparingnitrogen-containing heterocyclic compound of formula A andpharmaceutically acceptable salts thereof,

comprising the steps of:

(a) etherifying the hydroxy group of a compound of formula I or itsposition isomer with a compound of formula II wherein L₁ is a leavinggroup such as Cl and the like, which is less reactive than an etherforming leaving group L₂ such as Br and the like, or when n is 1, L₁ mayalso be —H, —CH═CH₂ or —C≡CH, or when n is 0 or 2, L₁ may also be —H;under basic etherification conditions, preferably wherein the base ispreferably potassium carbonate, sodium carbonate, sodium hydroxide andthe like, in the presence of an appropriate solvent such as toluene,methanol, ethanol, ether, THF and the like, preferably ethanol ortoluene, at reflux temperature of the solvent about 2-6 hours,preferably about 3 to 4 hours to produce a compound of formula III orits position isomer as follows:

(b) nitrating a compound according to formula III, or its positionisomer, to yield a compound according to formula IV, or its positionisomer, preferably at a temperature of from about 0° C. to 80° C.,preferably about 0° C. to 20° C. in nitric acid and an appropriatesolvent such as a mixture of acetic acid and dichloromethane, asfollows:

and when L₁ is a leaving group further comprising (c) reacting thecompound of formula IV, or its position isomer, with an amine containingcompound for the appropriate R³ group, such as a piperidine,pyrrolidine, morpholine, piperazine, 4-methyl piperidine or2-methyl-piperidine, in the presence of a basic catalyst such aspotassium carbonate, sodium carbonate, sodium hydroxide, and the like,preferably potassium carbonate and sodium iodine and a solvent such astoluene, ethanol, THF, ether, glyme, diglyme, MTBE, or the like, toreplace the L₁ group with an R³ group, and provide a compound of formulaV, or its position isomer, as follows:

(d) reducing the nitro group on the compound of formula V, or on itsposition isomer, to an amino group and thereby producing a compound offormula VI, or its position isomer, as follows:

(e) reacting the compound or formula VI, or its position isomer withammonium formate and formamide at about 120° C. to 140° C., preferably,at about 130° C. to produce a cyclized quinazoline derivative of formulaVII, or its position isomer, as follows:

f) replacing the hydroxy group of the compound of formula VII, or itsposition isomer, with a leaving group Q, preferably Q is the leavinggroups bromo, chloro, p-toluene sulfonate, methyl sulfonate and thelike, preferably chloro which is derived from a chlorinating agent suchas thionyl chloride, to provide a compound of formula VIII, or itsposition isomer, as follows:

(g) reacting the compound of formula VIII, or its position isomer withan amino group containing compound of the formula IX or a salt thereofto replace the leaving group Q and provide a compound of formula X, orits position isomer, as follows:

(h) and optionally, producing a salt, such as the hydrohalide salt, ofthe compound of formula X, or its position isomer, as follows:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention also provides a process for preparing an intermediatecompound having the formula VIII as follows:

wherein

-   n, R³ and R⁴ are defined as above, and-   Q is a leaving group other than a hydroxyl group, which can be    replaced by an amino group or other intermediary group which is to    be subsequently replaced by an amino group, or a salt thereof.

In the above process leaving groups such as halogen, lower alkoxy, loweralkylthio, lower alkylsulfonyloxy, arylsulfonyloxy, etc, may be utilizedwhen necessary except for the reaction point, followed by deprotection.Suitable amino protective groups are, for example, those described in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & SonsInc. (1981), etc., such as ethoxycarbonyl, t-butoxycarbonyl, acetyl,benzyl and the like which would be apparent to one of ordinary skill inthe art. The protective groups can be introduced and eliminatedaccording to conventional methods used in organic synthetic chemistry,e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons Inc. (1981).

Appropriate solvents include a lower alcohol, such as methanol, ethanol,isopropanol, etc., a halogenated hydrocarbon, such as chloroform,dichloromethane, etc., an aromatic hydrocarbon, such as benzene,toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., an aprotic polar solvent, such as dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixedsolvent thereof, optionally in the presence of a base. Examples of thebase include organic bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium carbonate, sodiumhydroxide, sodium hydride, etc., metal alkoxides, such as sodiummethoxide, potassium tert-butoxide, etc., and the like.

In such processes, if the defined groups change under the conditions ofthe working method or are not appropriate for carrying out the method,the desired compound can be obtained by using the methods forintroducing and eliminating protective groups which are conventionallyused in organic synthetic chemistry. See, e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons Inc. (1981), etc.Conversion of functional groups contained in the substituents can becarried out by known methods. See, e.g., R. C. Larock, ComprehensiveOrganic Transformations (1989), in addition to the above-describedprocesses, and some of the active compounds of formula I may be utilizedas intermediates for further synthesizing novel derivatives according toformula A.

The intermediates and the desired compounds in the processes describedabove can be isolated and purified by purification methodsconventionally used in organic synthetic chemistry, for example,neutralization, filtration, extraction, washing, drying, concentration,recrystallization, and various kinds of chromatography. Theintermediates may be subjected to the subsequent reaction withoutpurification.

There may be tautomers for some formula A, and the present inventioncovers all possible isomers including tautomers and mixtures thereof,the process of making would be apparent to one of ordinary skill in theart. Where chiral carbons lend themselves to two different enantiomers,both enantiomers are contemplated as well as procedures for separatingthe two enantiomers. In the compounds of this invention, carbon atomsbonded to four non-identical substituents are asymmetric. Accordingly,the compounds may also exist as diastereoisomers, enantiomers ormixtures thereof. The syntheses described herein may employ racemates,enantiomers or diastereomers as starting materials or intermediates.Diastereomeric products resulting from such syntheses may be separatedby chromatographic or crystallization methods, or by other methods knownin the art. Likewise, enantiomeric product mixtures may be separatedusing the same techniques or by other methods known in the art. Each ofthe asymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention. In the processes describedabove, the final products may, in some cases, contain a small amount ofdiastereomeric or enantiomeric products, however these products do notaffect their therapeutic or diagnostic application.

In the case where a salt of a compound of formula A is desired and thecompound is produced in the form of the desired salt, it can besubjected to purification as such. In the case where a compound offormula A is produced in the free state and its salt is desired, thecompound of formula A is dissolved or suspended in a suitable organicsolvent, followed by addition of an acid or a base to form a salt.Preferably the solvent for the recrystallization and salt formation is alower alcohol, preferably methanol or ethanol.

The following examples are provided to illustrate the invention. Theexamples are not intended to limit the scope of the present inventionand they should not be so interpreted. Amounts are in weight parts orweight percentages unless otherwise indicated. All of the cited patentsand publications are incorporated herein by reference. The followingspecific examples are provided to better assist the reader in thevarious aspects of practicing the present invention. As these specificexamples are merely illustrative, nothing in the following descriptionsshould be construed as limiting the invention in any way.

Such examples of the process according to the invention are merely anillustration of a preferred aspect of the invention. Other proceduresand adaptations will be apparent to one of ordinary skill in the artupon views these reaction schemes and the structures of the compoundsaccording to the invention. Such procedures are deemed to be within thescope of the present invention.

Also, the compounds of formula A and pharmaceutically acceptable saltsthereof may exist in the form of adducts with water (hydrates) orvarious solvents, which are also within the scope of the presentinvention.

The following non-limiting examples are provided to better illustratethe present invention.

EXAMPLE 1 Preparation of4-[6-Methoxy-7-(3-piperidin-1-yl-propoxy)-quinazolin-4-yl]-piperazine-1-carboxylicacid-4-(isopropoxy-phenyl)-amide

Step 1

Into a round bottom flask was charged 1-chloro3-bromopropane (1.28 mol)followed by a solution of aqueous potassium carbonate, ethyl vanillate(0.51 mol.) and N-butylammonium bromide (0.0255 mol.) and the resultingreaction mixture was heated to about 70 to about 100° C. for 0.5-4 hoursuntil reaction completion to compound III was confirmed by HPLC/TLCanalysis. The reaction mixture was cooled to about 20-25° C. anddichloromethane was added. The resulting biphasic mixture was separated.The organic layer was washed with water then brine solution and thesolvent was stripped under vacuum to approximately ⅕ of its originalvolume. This solution of compound III in dichloromethane was taken on tostep #2.

Step 2

Into a round bottom flask equipped with condenser, thermometer andoverhead stirrer was charged the solution of III in dichloromethanefollowed by acetic acid (0.5 L) and the resulting light brown solutionwas cooled to about 0-5° C. To the rapidly stirring solution was chargeddropwise 70% Nitric Acid (1.53 mol.) over about 40-60 minutes. Theresulting light brown solution was slowly heated to about 50-70° C. andwas allowed to stir at this temperature for about 2-10 hours untilreaction completion was confirmed by HPLC/TLC analysis. The orangecolored solution was poured into Ice/Water (1.0 L) and dichloromethane(0.5 L). The solution was allowed to warm to about 20° C., the layerswere separated and the organic layer was washed several times withde-ionized water followed by brine. The solvent was removed underreduced pressure to approximately ⅕ of the original volume at which timeethanol was introduced. The ethanolic solution was allowed to cool toabout 20° C. over 10-16 hours, then further cooled to about 0-10° C. forabout 1-3 hours. The off-white solid was collected by vacuum filtrationto give about 82% (based on starting weight of I) of IV. Productidentity was confirmed by proton NMR, carbon-13 and mass spectralanalysis.

Step 3

Into a round bottom flask was charged IV (0.31 mol) followed by toluene(500 ml), an aqueous potassium carbonate solution, N-butylammoniumbromide (0.0155 mol), sodium iodide (0.62 mol.) and piperidine (0.93mol) and the resulting reaction mixture was heated to about 60-100° C.for about 1-10 hours until reaction completion was confirmed by HPLC/TLCanalysis. The reaction mixture was cooled to about 20-25° C. and thelayers were separated. The aqueous layer was extracted once withtoluene. The combined organics were washed with water, 3% thiosulphatesolution and then brine. The toluene was removed under reduced pressureto approximately ⅕ of its original volume at which time ethanol (500ml), and water (200 ml) were added and V was taken in solution into step#4.

Step 4

Into a round bottom flask containing the solution of V inethanol/water/toluene was charged palladium on carbon catalyst (50% wet)and the reaction mixture was heated to about 40-50° C. To this warmedreaction mixture was charged a pre-made solution of potassium formate(0.62 mol) and formic acid (0.93 mol) in de-ionized water over about0.5-3 hours maintaining the solution temperature between 40-55° C. andthe solution pH between 3-6. The reaction mixture was allowed to stirfor about 0.5-4 hours at about 40-50° C. at which time HPLC/TLC analysisconfirmed reaction completion. The reaction mixture was filtered throughcelite. The filtrate was evaporated under atmospheric pressure until apot temperature of about 80-90° C. was reached. The remaining aqueoussolution was cooled to about 20-25° C. at which time ethyl acetate (600ml) was charged followed by an aqueous potassium carbonate solutionsufficient to adjust the pH to >10. After vigorous stirring the layerswere separated, the basic aqueous layer was extracted with ethyl acetateand the combined organic layers were washed with water followed by brinesolution. This ethyl acetate solution containing VI was taken directlyinto step #5

Step 5

To a round bottom flask containing VI (0.31 mol) in ethyl acetate andone equipped with mechanical stirrer, thermometer, and distillationapparatus was charged formamide (210 ml) and a distillation of ethylacetate was commenced until a pot temperature of about 120-130° C. wasreached. The reaction mixture was cooled to about 60-80° C. at whichtime ammonium formate (0.37 mol) was charged. The reaction mixture wasfurther heated to about 110-150° C. for about 2-12 hours, preferablyabout 130° C. for about six hours, until reaction completion wasconfirmed by HPLC/TLC analysis. The reaction mixture was cooled to about20-25° C. at which time diglyme (800 ml) followed by methyl t-butylether (260 ml) were charged in succession. The slurry was allowed tostir at about 20-25° C. for about 1-10 hours, preferably 3 hours, andwas then cooled to about 0-10° C. for about 1-3 hours. The product wasfiltered, the cake was washed with MTBE. The wet cake was transferred toanother round bottom flask and to the white product was charged MTBE(800 ml) and the slurry was stirred vigorously for about 1-4 hours atabout 20-25° C. The product was filtered and washed with MTBE then driedto a constant weight at about 30-50° C. under vacuum to give 70% yield(based on starting weight of IV) of VII. The identity of the product wasconfirmed by proton, C-13 NMR and mass spectral analysis.

Step 6

Into a round bottom flask equipped with overhead stirrer, thermometer,condenser and nitrogen purge was charged toluene (500 ml) followed byVII (0.28 mol)and the resulting suspension was cooled to about 0-10° C.at which time thionyl chloride (500 ml) was charged in portions overseveral hours maintaining the solution temperature of at least <25° C.The reaction mixture was re-cooled to about 10-15° C. at which timedimethyl formamide (100 ml) was charged in portions over several hoursmaintaining the solution temperature of at least <35° C. The reactionmixture was heated to about 80-85° C. where it was maintained for about1-5 hours until reaction completion was confirmed by HPLC/TLC analysis.To the reaction mixture was charged toluene (500 ml) maintaining thetemperature during the addition to at least >50° C. The reaction mixturewas allowed to cool to about 20-25° C. and was maintained at thistemperature for about 8-16 hours. The resulting precipitated solid wasfiltered and the cake was washed with toluene. The still toluene wetcake was added in portions to a pre-made solution of 20% potassiumbicarbonate and dichloromethane that was cooled to about 0-5° C. Afterensuring that a solution pH of at least >10 was obtained, the layerswere separated and the aqueous was extracted once more withdichloromethane. The combined organics were washed with water and thenbrine. The dichloromethane solution was evaporated under reducedpressure at temperature of at least <40° C. to approximately ⅕^(th) ofits original volume at which time acetonitrile (1800 ml) was charged.The resulting precipitated white solid was cooled to about 20-25° andwas allowed to stir at this temperature for about 4 hours. The productwas collected by filtration and washed with acetonitrile to give afterdrying to a constant weight in vacuo at about 35-50° C., 72% yield of atleast >95% VIII. The identity of this product was confirmed by proton,C-13 and mass spectral analysis.

Step 7

Into a round bottom flask equipped with mechanical stirrer, thermometer,reflux condenser and nitrogen purge was charged VIII (0.298 mol),dimethyl formamide (800 ml), potassium carbonate (0.746 mol)) and IX(0.300 mol) and the reaction mixture was stirred at about 20-50° C. forabout 2-24 hours, preferably about 6 hours at about 40° C., untilreaction completion was confirmed by HPLC/TLC analysis. The reactionmixture was cooled to about 20-25° C. at which time it was charged to asolution of de-ionized water and dichloromethane. The layers wereseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined and washed with 20% sodium chloridesolution, 20% ammonium chloride solution followed by brine. Thedichloromethane (DCM) was removed to approximately ⅕^(th) its originalvolume by evaporation under reduced pressure at a temperature of atleast <40° C. To this DCM solution was charged ethanol (1000 ml) and thesolution was heated to about 40-50° C. at which time charcoal was added.The reaction mixture was stirred at about 40-50° C. for about 0.5-1.0hours and was then filtered over celite to remove charcoal. The filtratewas re-heated to about 40° C. at which time a pre-made solution ofsulfuric acid in ethanol was added in portions until a solution pH ofabout 2-4 was reached. The resulting white slurry was cooled to about20-25° C. and stirred at this temperature for about 2-8 hours. It wasfurther cooled to about 0-10° C. where it was stirred for about 1-3hours. The product was collected by filtration and the cake was washedwith about 0-10° C. ethanol. The material was dried under vacuum atabout 40-50° C. until a constant weight was obtained to give an 80%yield of X with at least >90% purity by HPLC analysis.

Step 8

Into a round bottom flask equipped with mechanical stirrer, condenser,thermometer and argon purge was charged crude X (0.167 mol) followed byethanol (600 ml) and de-ionized water (200 ml). The reaction mixture washeated to about 55-60° C. at which time total dissolution was achieved.The solution was cooled to about 20-25° C. over at least 1-4 hours,preferably about 3 hours. The reaction mixture was further cooled toabout 0-5° C. where it was maintained for about 1-3 hours. The productwas collected by filtration, the cake was washed with about 0-5° C.ethanol and was then dried under vacuum at about 35-55° C., preferablyabout 45° C., until XI with an LOD <1% was obtained. Compound XI wasisolated in 83% yield and was found to be at least >99% purity by HPLCanalysis with no impurity of at least >0.5%. The identity of thiscompound was confirmed by comparison to a previously synthesized andfilly characterized analytical reference standard.

EXAMPLE 2 Preparation of4-[6-Methoxy-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-piperazine-1-carboxylicacid-(4-isopropoxy-phenyl)-amide

Step 1

Into a round bottom flask was charged 1-chloro3-bromopropane (1.53 mol)followed by a solution of aqueous potassium carbonate, ethyl vanillate(0.51 mol) and N-butylammonium bromide (0.0255 mol) and the resultingreaction mixture was heated to about 70-100° C. for about 0.5-4 hoursuntil reaction completion to the title compound was confirmed byHPLC/TLC analysis. The reaction mixture was cooled to about 20-25° C.and dichloromethane (500 ml) was added and the resulting biphasicmixture was separated. The organic layer was washed with water thenbrine solution and the solvent was stripped under vacuum toapproximately ⅕ of its original volume. This solution of compound III indichloromethane was taken on to step #2.

Step 2

Into a round bottom flask equipped with condenser, thermometer andoverhead stirrer was charged the solution of III (0.51 mol) indichloromethane followed by acetic acid (500 ml) and the resulting lightbrown solution was cooled to about 0-5° C. To the rapidly stirringsolution was charged dropwise 70% Nitric Acid (1.53 mol) over about40-60 minutes. The resulting light brown solution was slowly heated toabout 50-70° C. and was allowed to stir at this temperature for about2-10 hours until reaction completion was confirmed by HPLC/TLC analysis.The red colored solution was poured into Ice/Water (1000 ml) anddichloromethane (500 ml). The solution was allowed to warm to about 20°C., the layers were separated and the organic layer was washed severaltimes with de-ionized water followed by brine. The solvent was removedunder reduced pressure to approximately ⅕th of the original volume atwhich time ethanol was introduced. The solution was allowed to cool toabout 20° C. over about 10-16 hours, then further cooled to about 0-10°C. for about 1-3 hours. The off-white solid was collected by vacuumfiltration to give 82% (based on starting weight of I) of IV. Productidentity was confirmed by proton NMR, carbon-13 and mass spectralanalysis.

Step 3

Into a round bottom flask was charged IV (0.315 mol) followed by toluene(500 ml), an aqueous potassium carbonate solution, N-butylammoniumbromide (0.0158 mol), sodium iodide (0.48 mol) and morpholine (0.945mol) and the resulting reaction mixture was heated to about 60-100° C.for about 1-10 hours until reaction completion was confirmed by HPLC/TLCanalysis. The reaction mixture was cooled to about 20-25° C. and thelayers were separated. The aqueous layer was extracted once withtoluene. The combined organics were washed with water, 3% thiosulphatesolution and then brine. The toluene was removed under reduced pressureto approximately ⅕^(th) of its original volume at which time ethanol(500 ml), and water (200 ml) were added and V was taken in solution intostep #4.

Step 4

Into a round bottom flask containing the solution of V inethanol/water/toluene was charged palladium on carbon catalyst (50% wet)and the reaction mixture was heated to about 40-50° C. To this warmedreaction mixture was charged a pre-made solution of potassium formate(0.63 mol) and formic acid (0.945 mol) in de-ionized water over about0.5-3 hours maintaining the solution temperature between 40-55° C. andthe solution pH of at least between 3-6. The reaction mixture wasallowed to stir for about 0.5-4 hours at about 40-50° C. at which timeHPLC/TLC analysis confirmed reaction completion. The reaction mixturewas filtered through celite. The filtrate was evaporated underatmospheric pressure until a pot temperature of about 80-90° C. wasreached. The remaining aqueous solution was cooled to about 20-25° C. atwhich time ethyl acetate (500 ml) was charged followed by an aqueouspotassium carbonate solution sufficient to adjust the pH to atleast >10. After vigorous stirring the layers were separated, the basicaqueous layer was extracted with ethyl acetate and the combined organiclayers were washed with water followed by brine solution. This ethylacetate solution containing VI was taken directly into step #5.

Step 5

To a round bottom flask containing VI (0.315 mol) in ethyl acetate andone equipped with mechanical stirrer, thermometer, and distillationapparatus was charged formamide (210 ml) and a distillation of ethylacetate was commenced until a pot temperature of about 120-130° C. wasreached. The reaction mixture was cooled to about 60-80° C. at whichtime ammonium formate (0.378 mol) was charged. The reaction mixture wasfurther heated to about 110-150° C. for about 2-12 hours, preferablyabout 130° C. for about six hours, until reaction completion wasconfirmed by HPLC/TLC analysis. The reaction mixture was cooled to about20-25° C. at which time diglyme (800 ml) followed by methyl t-butylether (225 ml) were charged in succession. The slurry was allowed tostir at about 20-25° C. for about 1-10 hours, preferably about 3 hours,and was then cooled to about 0-10° C. for about 1-3 hours. The productwas filtered, the cake was washed with MTBE. The wet cake wastransferred to another round bottom flask and to the white product wascharged MTBE (800 ml) and the slurry was stirred vigorously for about1-4 hours at about 20-25° C. The product was filtered and washed withMTBE then dried to a constant weight at about 30-50° C. under vacuum togive at least 72% yield (based on starting weight of IV) of VII. Theidentity of the product was confirmed by proton, C-13 NMR and massspectral analysis.

Step 6

Into a round bottom flask equipped with overhead stirrer, thermometer,condenser and nitrogen purge was charged toluene (500 ml) followed byVII (0.278 mol.)and the resulting suspension was cooled to about 0-10°C. at which time thionyl chloride (500 ml) was charged in portions overseveral hours maintaining the solution temperature of at least <25° C.The reaction mixture was re-cooled to about 10-15° C. at which timedimethyl formamide (100 ml) was charged in portions over several hoursmaintaining the solution temperature of at least <35° C. The reactionmixture was heated to about 80-85° C. where it was maintained for about1-5 hours until reaction completion was confirmed by HPLC/TLC analysis.To the reaction mixture was charged toluene (500 ml) maintaining thetemperature during the addition to at least >50° C. The reaction mixturewas allowed to cool to about 20-25° C. and was maintained at thistemperature for about 8-16 hours. The resulting precipitated solid wasfiltered and the cake was washed with toluene. The still toluene wetcake was added in portions to a pre-made solution of 20% potassiumbicarbonate and dichloromethane that was cooled to about 0-5° C. Afterensuring that a solution pH of at least >10 was obtained, the layerswere separated and the aqueous was extracted once more withdichloromethane. The combined organics were washed with water and thenbrine. The dichloromethane solution was evaporated under reducedpressure at temperature of at least <40° C. to approximately ⅕^(th) ofits original volume at which time acetonitrile (1400 ml) was charged.The resulting precipitated white solid was cooled to about 20-25° andwas allowed to stir at this temperature for about 4 hours. The productwas collected by filtration and washed with acetonitrile to give afterdrying to a constant weight in vacuo at about 35-50° C., about 75% yieldof at least >95% VIII. The identity of this product was confirmed byproton, C-13 and mass spectral analysis.

Step 7

Into a round bottom flask equipped with mechanical stirrer, thermometer,reflux condenser and nitrogen purge was charged VIII (0.298 mol),dimethyl formamide (800 ml), potassium carbonate (0.745 mol) and IX(0.300 mol) and the reaction mixture was stirred at about 20-50° C. forabout 2-24 hours, preferably about 6 hours at about 40° C., untilreaction completion was confirmed by HPLC/TLC analysis. The reactionmixture was cooled to about 20-25° C. at which time it was charged to asolution of de-ionized water and dichloromethane. The layers wereseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined and washed with 20% sodium chloridesolution, 20% ammonium chloride solution followed by brine. Thedichloromethane was removed to approximately ⅕^(th) its original volumeby evaporation under reduced pressure at a temperature of at least <40°C. To this DCM solution was charged ethanol (800 ml) and the solutionwas heated to about 40-50° C. at which time charcoal was added. Thereaction mixture was stirred at about 40-50° C. for about 0.5-1.0 hoursand was then filtered over celite to remove charcoal. The filtrate wasre-heated to about 40° C. at which time a pre-made solution of sulfuricacid in ethanol was added in portions until a solution pH of at least2-3 was reached. The resulting white slurry was cooled to about 20-25°C. and stirred at this temperature for about 2-8 hours. It was furthercooled to about 0-10° C. where it was stirred for about 1-3 hours. Theproduct was collected by filtration and the cake was washed with about0-10° C. ethanol. The material was dried under vacuum at about 40-50° C.until a constant weight was obtained to give an 83% yield of X with atleast >90% purity by HPLC analysis.

Step 8

Into a round bottom flask equipped with mechanical stirrer, condenser,thermometer and argon purge was charged crude X (0.166 mol) followed bymethanol (600 ml) and de-ionized water (40 ml). The reaction mixture washeated to about 50-55° C. at which time total dissolution was achieved.The solution was cooled to about 20-25° C. over about 1-4 hours,preferably about 3 hours. The reaction mixture was further cooled toabout 0-5° C. where it was maintained for about 1-3 hours. The productwas collected by filtration and the cake was washed with about 0-5° C.methanol and was then dried under vacuum at about 35-55° C., preferably,about 45° C., until XI with an LOD of at least <1% was obtained.Compound XI was isolated in about 75% yield and was found to be atleast >99% pure by HPLC analysis with no impurity of at least >0.5%. Theidentity of this compound was confirmed by comparison to a previouslysynthesized and fully characterized analytical reference standard.

It is preferred to employ the administration route which is the mosteffective for the treatment. For example, administration is made orallyor non-orally by intrarectal, intraoral, subcutaneous, intramuscular orintravenous administration.

Examples of the forms for administration are capsules, tablets,granules, powders, syrups, emulsions, suppositories and injections.

Liquid compositions such as emulsions and syrups which are appropriatefor oral administration can be prepared using water, sugars such assucrose, sorbitol and fructose, glycols such as polyethylene glycol andpropylene glycol, oils such as sesame oil, olive oil and soybean oil,preservatives such as benzoates, flavors such as strawberry flavor andpeppermint, etc.

Capsules, tablets, powders and granules can be prepared using excipientssuch as lactose, glucose, sucrose and mannitol, disintegrating agentssuch as starch and sodium alginate, lubricants such as magnesiumstearate and talc, binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, surfactants such as fatty acid esters,plasticizers such as glycerin, etc.

Compositions for topical application are prepared by dissolving orsuspending an active compound in one or more kinds of solvents such asmineral oil, petroleum and polyhydric alcohol, or other bases used fortopical drugs.

Compositions for intestinal administration are prepared using ordinarycarriers such as cacao fat, hydrogenated fat and hydrogenated fatcarboxylic acid, and are provided as suppositories.

Compositions suitable for non-oral administration preferably comprise asterilized aqueous preparation containing an active compound which isisotonic to the recipient's blood. For example, injections are preparedusing a carrier which comprises a salt solution, a glucose solution, ora mixture of a salt solution and a glucose solution. The compositionsfor non-oral administration may additionally be formulated to containone or more kinds of additives selected from glycols, oils, flavors,preservatives (including antioxidants), excipients, disintegratingagents, lubricants, binders, surfactants and plasticizers which are usedfor the preparation of compositions for oral administration.

The effective dose and the administration schedule for each of thecompounds of formula (A) or a pharmaceutically acceptable salt thereofwill vary depending on the administration route, the patient's age andbody weight, and the type or degree of the diseases to be treated.However, it is generally appropriate to administer a compound of formula(A) or a pharmaceutically acceptable salt thereof in a dose of 0.01-1000mg/adult/day, preferably 5-500 mg/adult/day, in one to several parts.

All the compounds of the present invention produced by the processaccording to the invention can be immediately applied to the treatmentof kinase-dependent diseases of mammals as kinase inhibitors,specifically, those relating to tyrosine kinase. Specifically preferredare the compounds which have IC50 within the range of about 10 nM toabout 10 μm. Even more preferred are compounds which have IC50 withinthe range of about 10 nM to about 1 μM. Most preferred are compoundswhich have an IC50 value which is smaller than about 1 μM. Specificcompounds of the present invention which have an activity tospecifically inhibit one of the three types of protein kinase (forexample, kinase which phosphorylates tyrosine, kinase whichphosphorylates tyrosine and threonine, and kinase which phosphorylatesthreonine) can be selected. Tyrosine kinase-dependent diseases includehyperproliferative malfunction which is caused or maintained by abnormaltyrosine kinase activity.

Examples include psoriasis, pulmonary fibrosis, glomerulonephritis,cancers, atherosclerosis, and antiangiogenesis (e. g., tumorproliferation or diabetic retinopathy). Although relationships of otherclasses of kinase to specific diseases are not well known, it isconsidered that a selective tyrosine kinase-inhibiting compound has auseful therapeutic effect. Also, it is understood that other classes ofkinase have their own useful therapeutic effects. Quercetin, genisteinand staurosporin which are tyrosine kinase inhibitors inhibit many otherprotein kinase in addition to the tyrosine kinase, and have strongcytotoxicity as a result of the lack of specificity for them.Accordingly, tyrosine kinase inhibitors (or inhibitors of other kinase)which are apt to induce undesirable side effects due to lack ofselectivity can be identified using a usual test for measuringcytotoxicity.

The present invention provides a process for making nitrogen-containingheterocyclic compounds and pharmaceutically acceptable salts thereofwhich inhibit phosphorylation of PDGF receptor to hinder abnormal cellgrowth and thus, are useful for the prevention or treatment ofcell-proliferative diseases such as arteriosclerosis, vascularreobstruction, cancer and glomerulosclerosis. Other variations on theprocesses and compounds according to the invention will be apparent uponconsidering the preferred embodiments of the present invention and arehereby contemplated as being within the scope of the present invention.

Compositions or formulations of the compounds of the invention areprepared for storage or administration by mixing the compound having adesired degree of purity with physiologically acceptable carriers,excipients, stabilizers etc., and may be provided in sustained releaseor timed release formulations. Acceptable carriers or diluents fortherapeutic use are well known in the pharmaceutical field, and aredescribed, for example, in Remington's Pharmaceutical Sciences, MackPublishing Co., (A. R. Gennaro edit. 1985). Such materials are nontoxicto the recipients at the dosages and concentrations employed, andinclude buffers such as phosphate, citrate, acetate and other organicacid salts, antioxidants such as ascorbic acid, low molecular weight(less than about ten residues) peptides such as polyarginine, proteins,such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymerssuch as polyvinylpyrrolidinone, amino acids such as glycine, glutamicacid, aspartic acid, or arginine, monosaccharides, disaccharides, andother carbohydrates including cellulose or its derivatives, glucose,mannose or dextrins, chelating agents such as EDTA, sugar alcohols suchas mannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as TWEEN®, PLURONICS® or polyethyleneglycol.

The term “effective amount” is an amount necessary for administering thecompound in accordance with the present invention to provide thenecessary effect such as inhibiting the phosphorylation of kinases ortreating disease states in a mammal. In accordance with the presentinvention, a suitable single dose size is a dose that is capable ofpreventing or treating an animal with a disease when administered one ormore times over a suitable time period. Doses can vary depending uponthe disease being treated. For example, in the treatment ofhypersensitivity, a suitable single dose can be dependent upon thenature of the immunogen causing the hypersensitivity.

An effective administration protocol (i.e., administering a therapeuticcomposition in an effective manner) comprises suitable dose parametersand modes of administration that result in prevention or treatment of adisease. Effective dose parameters and modes of administration can bedetermined using methods standard in the art for a particular disease.Such methods include, for example, determination of survival rates, sideeffects (i.e., toxicity) and progression or regression of disease. Forexample, the effectiveness of dose parameters and modes ofadministration of a therapeutic composition of the present invention canbe determined by assessing response rates. Such response rates refer tothe percentage of treated patients in a population of patients thatrespond with either partial or complete remission.

Dosage formulations of the compounds of the invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of the invention typically will be about 3-11, morepreferably about 5-9 and most preferably about 7-8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of cyclic polypeptide salts.While the preferred route of administration is by injection, othermethods of administration are also anticipated such as orally,intravenously (bolus and/or infusion), subcutaneously, intramuscularly,colonically, rectally, nasally, transdermally or intraperitoneally,employing a variety of dosage forms such as suppositories, implantedpellets or small cylinders, aerosols, oral dosage formulations andtopical formulations such as ointments, drops and dermal patches. Thecompounds of the invention are desirably incorporated into shapedarticles such as implants which may employ inert materials such asbiodegradable polymers or synthetic silicones, for example, Silastic,silicone rubber or other polymers commercially available.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of the invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of the invention may also be coupled with suitable polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidinone, pyran copolymer,polyhydroxypropyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels. Polymers and semipermeablepolymer matrices may be formed into shaped articles, such as valves,stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill be influenced by the route of administration, the therapeuticobjectives and the condition of the patient. For injection by hypodermicneedle, it may be assumed the dosage is delivered into the body'sfluids. For other routes of administration, the absorption efficiencymust be individually determined for each compound by methods well knownin pharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be readily determined by one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

The compounds and compositions of the invention can be administeredorally or parenterally in an effective amount within the dosage range ofabout 0.001 to about 1000 mg/kg, preferably about 0.01 to about 100mg/kg and more preferably about 0.1 to about 20 mg/kg. Advantageously,the compounds and composition of the invention may be administeredseveral times daily. Other dosage regimens may also be useful (e.g.single daily dose and/or continuous infusion).

Typically, about 0.5 to about 500 mg of a compound or mixture ofcompounds of the invention, as the free acid or base form or as apharmaceutically acceptable salt, is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, dye, flavor etc., as called for by accepted pharmaceuticalpractice. The amount of active ingredient in these compositions is suchthat a suitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are binders such as acacia, corn starch or gelatin, andexcipients such as microcrystalline cellulose, disintegrating agentslike corn starch or alginic acid, lubricants such as magnesium stearate,sweetening agents such as sucrose or lactose, or flavoring agents. Whena dosage form is a capsule, in addition to the above materials it mayalso contain liquid carriers such as water, saline, or a fatty oil.Other materials of various types may be used as coatings or as modifiersof the physical form of the dosage unit. Sterile compositions forinjection can be formulated according to conventional pharmaceuticalpractice. For example, dissolution or suspension of the active compoundin a vehicle such as an oil or a synthetic fatty vehicle like ethyloleate, or into a liposome may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides,alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, orisethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates ornapsylates, phosphates, sulphates, hydrogen sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts. Prodrugs of compoundsof formula (1) include those compounds, for example esters, alcohols oraminos, which are convertible in vivo by metabolic means, e.g. byhydrolysis, reduction, oxidation or transesterification, to compounds offormula (1). Particularly useful salts of compounds according to theinvention include pharmaceutically acceptable salts, especially acidaddition pharmaceutically acceptable salts. Next, the pharmacologicalactivity of the compounds of the present invention are specificallyexplained by test examples.

The pharmacological activities of the compounds of the present inventionare obtained by following the test example procedures as follows, forexample.

Biological Test Assay Type 1

Inhibitory Effect on Compounds on Autophosphorylation of PlateletDerived Growth Factor β-PDGF Receptor

(1) HR5 Phosphorylation Assay

The HR5 cell line is a cell line of CHO cells engineered to overexpresshuman β-PDGFR, which cell line is available from the ATCC. Theexpression level of β-PDGFR in HR5 cells is around 5×10⁴ receptor percell. For the phosphorylation assay according to the invention, HR5cells were grown to confluency in 96-well microtiter plates understandard tissue culture conditions, followed by serum-starvation for 16hours. Quiescent cells were incubated at 37° C. without or withincreasing concentrations of the test compound (0.01-30 uM) for 30minutes followed by the addition of 8 nM PDGF BB for 10 minutes. Cellswere lysed in 100 mM Tris, pH7.5, 750 mM NaCl, 0.5% Triton X-100, 10 mMsodium pyrophosphate, 50 mM NaF, 10 ug/ml aprotinin, 10 ug/ml leupeptin,1 mM phenylmethylsulfonyl fluoride, 1 mM sodium vanadate, and the lysatewas cleared by centrifugation at 15,000×g for 5 minutes. Clarifiedlysates were transferred into a second microtiter plate in which thewells were previously coated with 500 ng/well of 1B5B11 anti-β-PDGFRmAb, and then incubated for two hours at room temperature. After washingthree times with binding buffer (0.3% gelatin, 25 mM Hepes pH 7.5, 100mM NaCl, 0.01% Tween-20), 250 ng/ml of rabbit polyclonalanti-phosphotyrosine antibody (Transduction Laboratory) was added andplates were incubated at 37° C. for 60 minutes. Subsequently, each wellwas washed three times with binding buffer and incubated with 1 ug/ml ofhorse radish peroxidase-conjugated anti-rabbit antibody (BoehringerMannheim) at 37° C. for 60 minutes. Wells were washed prior to addingABTS (Sigma), and the rate of substrate formation was monitored at 650nm. The assay results are reported as IC₅₀ (expressed as theconcentration of a compound according to the invention that inhibits thePDGF receptor phosphorylation by 50%) as compared to control cells thatare not exposed to a compound according to the invention.

Examples of such IC₅₀ test results in the HR5 assay for compoundsaccording to the invention are set forth below in Table 1.

(1) MG63 Phosphorylation Assay

The MG63 cell line is a human osteosarcoma tumor cell line availablefrom the ATCC. This assay is for measuring endogenous β-PDGFRphosphorylation in MG63 cells. The assay conditions are the same asthose described at for HR5 cell, except that PDGF-BB stimulation isprovided in the presence or absence of 45% human plasma. The HR5 assayresults are reported as an IC₅₀ (expressed as the concentration of acompound according to the invention that inhibits the PDGF receptorphosphorylation by 50%) as compared to control cells that are notexposed to a compound according to the invention.

Examples of such IC₅₀ test results in the MG63 assay for compoundsaccording to the invention are set forth below in Table 1.

The assay results for Compound Examples 2 1 and 4 2 are set forth inTable 1 below.

TABLE 1 MG63 w/human plasma HR5 Example Compound IC50(μM) IC50(μM)Example 1 0.030 0.250 Example 2 0.060 0.130Biological Test Assay Type 2Growth Inhibition Against Smooth Muscle Cells

Vascular smooth muscle cells are isolated from a pig aorta byexplanation and used for the test. The cells are put into wells of a96-well plate (8000 cells/well) and cultured in Dulbeccois modifiedEagle's medium (DMEM; Nissui Pharmaceutical Co., Ltd.) containing 10%fetal bovine serum (FBS; Hyclone) for 4 days. Then, the cells arefurther cultured in DMEM containing 0.1% FBS for 3 days, and aresynchronized at the cell growth stationary phase.

To each well is added DMEM containing 0.1% FBS and a test sample at avaried concentration, and the cell growth is brought about by PDGF-BB(SIGMA, final concentration: 20 ng/ml). After culturing for 3 days, thecell growth is measured using a cell growth assay kit (BoehringerMannheim) according to the XTT method [J. Immunol. Methods, 142, 257-265(1991)], and the cell growth score is calculated by the followingequation.

Cell growth score=100×{1-(M-PO)/(P100-PO)} wherein P100=absorbance byXTT reagent when stimulated by PDGF-BB; PO=absorbance by XTT reagentwhen not stimulated by PDGF-BB, and M=absorbance by XTT reagent afteraddition of a sample when stimulated by PDGF-BB.

The test result is expressed as the concentration of a test compoundwhich inhibits the cell growth by 50% (IC50).

Biological Test Assay Type 3

Inhibitory Effect on Hypertrophy of Vascular Intima

Male SD rats (weight: 375-445 g, Charles River, golden standard) areanesthetized with sodium pentobarbital (50 mg/kg, i.p.), and then theneck of each animal is incised by the median incision, followed byretrograde insertion of a balloon catheter (2F, Edwards Laboratories)into the left external carotid. After the above treatment is repeatedseven times, the catheter is pulled out, the left external carotid isligated, and the wound is sutured. A test compound is suspended in a0.5% solution of Tween 80 in an aqueous solution of sodium chloride to aconcentration of 20 mg/ml in the case of intraperitoneal administrationand in a 0.5% solution of methyl cellulose 400 to a concentration of 6mg/ml in the case of oral administration. The suspension is administeredonce a day in the case of intraperitoneal administration and once ortwice a day in the case of oral administration for a period of 15 daysstarting on the day before the balloon injury. On the 14th day after theballoon injury, the animal is killed and its left carotid is extirpated.The tissues are fixed with formalin, wrapped in paraffin and sliced,followed by Elastica Wangeeson staining. The area of the cross sectionof the vascular tissues (intima and media) is measured with an imageanalyzer (Luzex F, NIRECO) and the intima/media area ratio (I/M) isregarded as the degree of hypertrophy of the vascular intima.

From the results obtained, it is apparent when the hypertrophy ofvascular intima is significantly inhibited by administration of thecompounds of the present invention.

Biological Test Assay Type 4

Evaluation by the Use of a Rat Adjuvant Arthritis Model

Dead cells of Mycobacterium bacterium (Difco Laboratories Inc.) aredisrupted in agate mortar and suspended in liquid paraffin to the finalconcentration of 6.6 mg/ml, followed by sterilization with high pressuresteam. Then, 100 ml of the suspension is subcutaneously injected intothe right hind foot pad of each animal of groups of female 8-weeks-oldLewis rats (Charles River Japan) (6 animals/group) to induce adjuvantarthritis. A test compound is suspended in a 0.5% solution of methylcellulose to the final concentration of 3 mg/ml, and from just beforethe induction of arthritis, the suspension is orally administered in anamount of 100 ml/100 g of the body weight once a day, 5 days a week. Toa control group is administered a 0.5% solution of methyl cellulose. Anormal group is given no adjuvant treatment or test compoundadministration. The administration of the test compound is continuedtill the 18th day after the adjuvant treatment. On the 17th day, thenumber of leukocytes in peripheral blood are counted, and on the 18thday, all the blood is collected, followed by dissection.

The change in body weight with the passage of time, the change of edemain hind foot with the passage of time, the weight of spleen and thymus,the number of leukocytes in peripheral blood, the hydroxyproline contentof urine, the glucosaminoglycan content of urine, the SH concentrationin serum, the concentration of nitrogen monoxide in serum and theconcentration of mucoprotein in serum are measured and evaluated. Thevolume of each of both hind feet are measured using a rat's hind footedema measurement device (TK-101, Unicorn). The number of leukocytes inperipheral blood are counted using an automatic multichannel blood cellcounter (Sysmex K-2000, Toa Iyo Denshi Co., Ltd.). The hydroxyprolinecontent of urine is measured according to the method described in Ikeda,et al., Annual Report of Tokyo Metropolitan Research Laboratories P. H.,36, 277 (1985), and the glucosaminoglycan content is measured accordingto the method described in Moriyama, et al., Hinyo Kiyo, 40, 565 (1994)and Klompmakers, et al., Analytical Biochemistry, 153, 80 (1986). The SHconcentration in serum is measured according to the method described inMiesel, et al., Inflammation, 17, 595 (1993), and the concentration ofnitrogen monoxide is measured according to the method of Tracey, et al.,Journal of Pharmacology & Experimental Therapeutics, 272, 1011 (1995).The concentration of mucoprotein is measured using Aspro GP Kit (OtsukaPharmaceutical Co., Ltd.). The percentage inhibition for each indicationis calculated according to the following equation.% Inhibition={(Control group−Compound-administered group)/(Controlgroup−Normal group)}×100.

From the results obtain from such assays, it is apparent when thecompound according to the invention inhibits the occurrence of adjuvantarthritis.

Biological Test Assay Type 5

Activity on a Mesangial Proliferative Glomerulonephritis Model

Anti-rat Thy-1.1 monoclonal antibody OX-7 (Sedaren) is administered tomale Wister-Kyoto rats (Charles River Japan, 160 g, 6 animals/group) inan amount of 1.0 mg/kg by intravenous administration through the tailvein. A test compound is suspended in a 0.5% solution of methylcelluloseand the resulting suspension is administered to each of the rats twice aday for a period of 7 days starting on the day before the administrationof OX-7. On the 7th day after the OX-7 administration, when mesangialcell growth and extracellular matrix hypertrophy become prominent, theleft kidney of each rat is extirpated, fixed with 20% buffered formalinfor 6 hours and wrapped in paraffin, followed by slicing. The obtainedpieces are subjected to immune tissue staining using antibody PC10(DAKO) against an intranuclear antigen of proliferative cells. Aftercomparative staining with Methyl Green staining solution usingdiaminobenzidine as a color developer, the paraffin pieces are enclosed.Half of the glomeruli in a kidney piece are observed and the number ofthe cells in one glomerulus which are positive to the intranuclearantigen of proliferative cells are calculated. The test for thesignificance of difference is carried out by the Wilcoxon test.

From such results, it is apparent when the compounds according to thepresent invention show alleviating activity on mesangial proliferativeglomerulonephritis.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. The examples given above are non-limiting in thatone of ordinary skill in view of the above will readily envision otherpermutations and variations on the invention without departing from theprincipal concepts. Such permutations and variations are also within thescope of the present invention. All the patents, journal articles andother documents discussed or cited above are herein incorporated byreference. The invention is further illustrated with reference to theclaims that follow thereto.

1. A process for preparing a compound of formula A:

wherein R¹is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising the steps of: (a) etherifyingthe hydroxy group of a compound of formula I or its position isomer witha compound of formula II wherein L₁ is a leaving group, under basicetherification conditions in the presence of an appropriate solvent toproduce a compound of formula III or its position isomer as follows:

(b) nitrating the compound according to formula III, or its positionisomer, to yield a compound according to formula IV, or its positionisomer, at a suitable temperature in a solvent as follows:

(c) reacting the compound of formula IV, or its position isomer, with anamine containing compound selected from the group consisting ofpiperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and2-methyl-piperidine, in the presence of a catalyst and a solvent toprovide a compound of formula V, or its position isomer, as follows:

(d) reducing the nitro group on the compound of formula V, or on itsposition isomer, to an amino group and thereby producing a compound offormula VI, or its position isomer, as follows:

(e) reacting the compound of formula VI, or its position isomer withammonium formate and formamide at a suitable temperature to produce acyclized quinazoline derivative of formula VII, or its position isomer,as follows:

(f) replacing the hydroxy group of the compound of formula VII, or itsposition isomer, with a leaving group Q to provide a compound of formulaVIII, or its position isomer, as follows:

(g) reacting the compound of formula VIII, or its position isomer, witha compound of the formula IX, or a salt thereof, to provide a compoundof formula X, or its position isomer, as follows:

(h) and optionally, producing a salt, solvate, hydrate, or N-acylated,of the compound of formula X, or its position isomer.
 2. The processaccording to claim 1 wherein the leaving group L₁ in step (a) isselected from the group consisting of Cl, Br, p-toluenesulfonate andmethyl sulfonate.
 3. The process according to claim 1 wherein theleaving group L₂ in step (a) is selected from the group consisting ofCl, Br, p-toluenesulfonate and methyl sulfonate.
 4. The processaccording to claim 1 wherein the solvent in step (a) is selected fromthe group consisting of toluene, methanol, ethanol, ether, and THF. 5.The process according to claim 1 wherein the base in step (a) isselected from the group consisting of potassium carbonate, sodiumcarbonate, and sodium hydroxide.
 6. The process according to claim 1wherein step (a) is conducted for about 2 to about 6 hours.
 7. Theprocess according to claim 1 wherein the compound in step (b) isnitrated at a temperature of from about 0 to about 80° C.
 8. The processaccording to claim 1 wherein the catalyst in step (c) is selected fromthe group consisting of potassium carbonate, sodium carbonate, sodiumhydroxide, and sodium iodide.
 9. The process according to claim 1wherein the solvent in step (c) is selected from the group consisting oftoluene, ethanol, ether, THF, glyme, diglyme, and MTBE.
 10. The processaccording to claim 1 wherein cyclization step (e) is conducted at atemperature of about 100° C. to about 200° C.
 11. The process accordingto claim 1 wherein the leaving group Q is selected from the groupconsisting of Cl, Br, p-toluene sulfonate and methyl sulfonate.
 12. Theprocess according to claim 1 wherein R³ in compound of Formula A is amember selected from the group consisting of piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 13. The process according to claim 12wherein R¹ is a member selected from the group consisting of CN and—O-isopropyl, n is 2 or 3, and R³ is selected from the group consistingof piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidineand 2-methyl-piperidine, and position isomers and homologues thereof,and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand N-acylated derivatives thereof.
 14. The process according to claim12, wherein R¹ is a member selected from the group consisting of CN and—O-isopropyl, n is 2 or 3, and R³ is a substituted or unsubstitutedpiperidinyl or pyrrolidinyl radical, and position isomers and homologuesthereof, and all pharmaceutically acceptable isomers, salts, hydrates,solvates and N-acylated derivatives thereof.
 15. The process accordingto claim 1 which is a process for making a compound according to formulaA(1) or formula A(2):

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts,hydrates, solvates and N-acylated derivatives thereof.
 16. The processaccording to claim 15, wherein R¹ is —O-isopropyl or CN, n is 2 or 3,and R³ is selected from the group consisting of piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 17. The process according to claim 15,wherein n is 3, R¹ is —O-isopropyl or CN and R³ is a member selectedfrom the group consisting of; piperidine, pyrrolidine, morpholine,piperazine, 4-methyl-piperidine and 2-methyl-piperidine and allpharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 18. The process according to claim 15,wherein n is 3, R¹ is —O-isopropyl or CN and R³ is selected from thegroup consisting of piperidine, pyrrolidine, morpholine, piperazine,4-methyl-piperidine and 2-methyl-piperidine and all pharmaceuticallyacceptable isomers, salts, hydrates, solvates and N-acylated derivativesthereof.
 19. The process according to claim 18, wherein n is 3, R¹ is—O-isopropyl or CN and R³ is N-piperidine or N-pyrrolidine, and allpharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 20. A process for preparing anintermediate compound having formula VIII, comprising the step ofreplacing the hydroxy group of the compound of formula VII, or itsposition isomer, with a leaving group Q to provide a compound of formulaVIII, or its position isomer, as follows:

wherein n, R³ and R⁴ are defined as in claim 1, and Q is a leaving groupother than a hydroxyl group, which can be replaced by an amino group orother intermediary group which is subsequently replaced by an aminogroup, or a salt thereof.
 21. A process for preparing a compound offormula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising: etherifying the hydroxygroup of a compound of formula I or its position isomer with a compoundof formula II wherein L₁ is a leaving group, under basic etherificationconditions in the presence of an appropriate solvent to produce acompound of formula III or its position isomer as follows:


22. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O-CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n) —R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n)—R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising: nitrating the compoundaccording to formula III, or its position isomer, to yield a compoundaccording to formula IV, or its position isomer, at a suitabletemperature in solvent as follows:


23. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising: reacting the compound offormula IV, or its position isomer, with an amine containing compoundselected from the group consisting of piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine forthe appropriate R³ group, in the presence of a basic catalyst and asolvent to replace the L₁ group with an R³ group, and provide a compoundof formula V, or its position isomer, as follows:


24. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH2—CH═CH₂, —O—CH₂C═CH and —O(—CH₂)_(n)—R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n)—R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising: reducing the nitro group onthe compound of formula V, or on its position isomer, to an amino groupand thereby producing a compound of formula VI, or its position isomer,as follows:


25. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy5-isoquinolyloxy; R² and R⁴ are each independently a member selectedfrom the group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃,—O(—CH₂)₂—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; whereinone of the R² and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² orR⁴ group is other than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ a memberselected from the group consisting of: piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, andall pharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof, comprising: reacting the compound offormula VI, or its position isomer with ammonium formate and formamideat a suitable temperature to produce a cyclized quinazoline derivativeof formula VII, or its position isomer, as follows:


26. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy R² and R⁴ are each independently a member selected fromthe group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃, —O(—CH₂)₂—CH₃,—O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; wherein one of the R²and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² or group is otherthan —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a member selected from thegroup consisting of: piperidine, pyrrolidine, morpholine, piperazine,4-methyl-piperidine and 2-methyl-piperidine, and all pharmaceuticallyacceptable isomers, salts, hydrates, solvates and N-acylated derivativesthereof, comprising: replacing the hydroxy group of the compound offormula VII, or its position isomer, with a leaving group Q to provide acompound of formula VIII, or its position isomer, as follows:


27. A process for preparing a compound of formula A:

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy R² and R⁴ are each independently a member selected fromthe group consisting of: hydrogen, —O—CH₃, —O(—CH₂)—CH₃, —O(—CH₂)₂—CH₃,—O—CH₂—CH═CH₂, —O—CH₂—C═CH and —O(—CH₂)_(n)—R³; wherein one of the R²and R⁴ groups is —O(—CH₂)_(n) —R³ and the remaining R² or R⁴ group isother than —O(—CH₂)_(n)—R³; n is 2 to 5; R³ is a member selected fromthe group consisting of: piperidine, pyrrolidine, morpholine, piperazine4-methyl-piperidine and 2-methyl-piperidine, and all pharmaceuticallyacceptable isomers, salts, hydrates, solvates and N-acylated derivativesthereof, comprising: reacting the compound of formula VIII, or itsposition isomer, with a compound of the formula IX, or a salt thereof,to provide a compound of formula X, or its position isomer, as follows:


28. The process of claim 27 further comprising producing a salt,solvate, hydrate or prodrug of the compound of formula X.
 29. Theprocess of claim 28 further comprising producing a salt, hydrate, orcombination thereof of the compound of formula X.
 30. The processaccording to claim 27 which is a process for making a compound accordingto formula A(1) or formula A(2):

wherein R¹ is a member selected from the group consisting of: —CN,—O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl,—O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts,hydrates, solvates and N-acylated derivatives thereof.
 31. The processaccording to claim 30, wherein R¹ is —O-isopropyl or CN, n is 2 or 3,and R³ is a member selected from the group consisting of piperidine,pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and2-methyl-piperidine, as well as position isomers and homologues thereof,and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand N-acylated derivatives thereof.
 32. The process according to claim30, wherein n is 3, R¹ is —O-isopropyl or CN and R³ a member selectedfrom the group consisting of: piperidine, pyrrolidine, morpholine,piperazine, 4-methyl-piperidine and 2-methyl-piperidine and allpharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 33. The process according to claim 30,wherein n is 2, R¹ is —O-isopropyl or CN and R³ is selected from thegroup consisting of: piperidine, pyrrolidine, morpholine, piperazine,4-methyl-piperidine and 2-methyl-piperidine and all pharmaceuticallyacceptable isomers, salts, hydrates, solvates and N-acylated derivativesthereof.
 34. The process according to claim 18, wherein n is 3, R¹ is—O-isopropyl or CN and R³ is N-piperidine or N-morpholine, and allpharmaceutically acceptable isomers, salts, hydrates, solvates andN-acylated derivatives thereof.
 35. A process for preparing a compoundof formula X:

and all pharmaceutically acceptable salts and hydrates thereof whereinR¹ is a member selected from the group consisting of: —CN, —O-methyl,—O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl,1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indoylyoxy,5-isoquinolyloxy; R⁴ is selected from the group consisting of: hydrogen,—O-CH₃, —O(—CH₂) —CH₃, —O(—CH₂)₂ —CH₃, —O—CH₂ —CH═CH₂, —O—CH₂—C≡CH; n is2 to 5; R³ is a member selected from the group consisting of:piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and2-methyl-piperidine, and all pharmaceutically acceptable salts andhydrates thereof, comprising the steps of: (a) etherifying the hydroxygroup of a compound of formula I with a compound of formula II, underbasic etherification conditions in the presence of an appropriatesolvent to produce a compound of formula III as follows:

(b) nitrating the compound according to formula III to yield a compoundaccording to formula IV at a suitable temperature in a solvent asfollows:

(c) reacting the compound of formula IV with an amine containingcompound selected from the group consisting of piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, inthe presence of a catalyst and a solvent to provide a compound offormula V as follows:

(d) reducing the nitro group on the compound of formula V to an aminogroup and thereby producing a compound of formula VI as follows:

(e) reacting the compound of formula VI with ammonium formate andformamide at a suitable temperature to produce a cyclized quinazolinederivative of formula VII as follows:

(f) replacing the hydroxy group of the compound of formula VII with aleaving group Q to provide a compound of formula VIII as follows:

(g) reacting the compound of formula VIII with a compound of the formulaIX, or a salt thereof, to provide a compound of formula X as follows:

(h) and optionally, producing a salt or hydrate of the compound offormula X and each L₁, L₂ or Q is a leaving group, independentlyselected from the group consisting of halogen, alkoxy, aryloxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy andarylsulfonyloxy.
 36. A process for preparing a compound of formula X:

and all pharmaceutically acceptable salts and hydrates thereof, whereinR¹ is a member selected from the group consisting of: —CN, —O-methyl,—O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl,1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy,5-isoquinolyloxy; R⁴ is a member selected from the group consisting of:hydrogen, —O—CH₃, —O(—CH₂) —CH₃, —O(—CH₂)₂ —CH₃, —O—CH₂ —CH═CH₂, —O—CH₂—C≡CH and —O(—CH₂)_(n) —R³; n is 2 to 5; R³ is a member selected fromthe group consisting of: piperidine, pyrrolidine, morpholine,piperazine, 4-methyl-piperidine and 2-methyl-piperidine, comprising atleast one of: (a) etherifying the hydroxy group of a compound of formulaI with a compound of formula II, under basic etherification conditionsin the presence of an appropriate solvent to produce a compound offormula III as follows:

(b) nitrating the compound according to formula III to yield a compoundaccording to formula IV at a suitable temperature in a solvent asfollows:

(c) reacting the compound of formula IV with an amine containingcompound selected from the group consisting of piperidine, pyrrolidine,morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, inthe presence of a catalyst and a solvent to provide a compound offormula V as follows:

(d) reducing the nitro group on the compound of formula V to an aminogroup and thereby producing a compound of formula VI as follows:

(e) reacting the compound of formula VI with ammonium formate andformamide at a suitable temperature to produce a cyclized quinazolinederivative of formula VII as follows:

(f) replacing the hydroxy group of the compound of formula VII with aleaving group Q to provide a compound of formula VIII as follows:

 and further converting the product of said step(s) to a compound offormula X or (g) reacting the compound of formula VIII with a compoundof the formula IX, or a salt thereof, to provide a compound of formula Xas follows:

 wherein each of L₁, L₂ or Q is independently selected from the groupconsisting of halogen, alkoxy, aryloxy, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy.
 37. The process ofclaim 36, wherein R⁴ is —O—CH₃.
 38. The process of claim 36, wherein R¹is —O-isopropyl or —CN.
 39. The process of claim 36, wherein n is 3 andR³ is N-piperidine, N-pyrrolidine or morpholine.
 40. The processaccording to claim 36, wherein each leaving group L₁, L₂ or Q isindependently selected from the group consisting of Cl, Br,p-toluenesulfonyloxy and methyl sulfonyloxy.
 41. The process accordingto claim 36, wherein the solvent in step (a) is selected from the groupconsisting of toluene, methanol, ethanol, ether, and THF.
 42. Theprocess according to claim 36, wherein the base in step (a) is selectedfrom the group consisting of potassium carbonate, sodium carbonate, andsodium hydroxide.
 43. The process according to claim 36, wherein step(a) is conducted for about 2 to about 6 hours.
 44. The process accordingto claim 36, wherein the compound in step (b) is nitrated at atemperature of from about 0° C. to about 80° C.
 45. The processaccording to claim 36, wherein the catalyst in step (c) is selected fromthe group consisting of potassium carbonate, sodium carbonate, sodiumhydroxide, and sodium iodide.
 46. The process according to claim 36,wherein the solvent in step (c) is selected from the group consisting oftoluene, ethanol, ether, THF, glyme, diglyme, and MTBE.
 47. The processaccording to claim 36, wherein cyclization step (e) is conducted at atemperature of about 100° C. to about 200° C.
 48. The process accordingto claim 36, wherein R¹ is selected from the group consisting of —CN and—O-isopropyl and n is 2 or
 3. 49. The process according to claim 36,wherein R¹ is selected from the group consisting of —CN and—O-isopropyl, n is 2 or 3, and R³ is piperidine or pyrrolidine.
 50. Theprocess according to claim 36, wherein n is 2 and R¹ is —O-isopropyl or−CN.
 51. The process according to claim 36, wherein R⁴ is —O—CH₃, n is 3and R¹ is —O-isopropyl or —CN.
 52. The process according to claim 51,wherein R³ is


53. The process of claim 36 further comprising producing a salt orhydrate of the compound of formula X.
 54. The process of claim 36further comprising producing a salt, hydrate, or combination thereof ofthe compound of formula X.